Subunit vaccines based on self-assembled major capsid proteins synthesised in heterologous cells, have proven effective in preventing infection by several pathogenic viruses, including hepatitis B virus and human papillomavirus. The use of viral capsomeres as subunit vaccines affords a number of advantages because they should result in highly homogeneous vaccine compositions. Moreover, capsomeres are considered to be a cost-effective alternative to VLP-based vaccines because they can be produced in relatively cost effective expression systems (such as bacterial expression systems) and because of their high degree of stability. In particular, if the capsomeres do not give rise to virus-like particles (VLPs) or other aggregates to any significant extent, compositions comprising such capsomeres should be substantially free of higher molecular weight forms of the capsid proteins. This is advantageous from a clinical standpoint wherein supplying a product of high consistency may be very important, indeed essential. That is, capsomeres may give rise to pharmaceutical compositions and in particular vaccines, of enhanced homogeneity. Also, since capsomeres are significantly smaller than VLPs, they may be easier to purify on conventional chromatographic media, thereby increasing the ease of manufacture.
Vaccine formulations comprising chimeric capsomeres can provide an advantage of increased antigenicity of both protein components of the fusion protein from which the capsomere is formed. For example, in a VLP, protein components of the underlying capsomere may be buried in the overall structure as a result of internalized positioning within the VLP itself. Similarly, epitopes of the protein components may be sterically obstructed as a result of capsomere-to-capsomere contact, and therefore unaccessible for eliciting an immune response. Capsomere vaccines potentially offer the additional advantage of increased antigenicity against any protein component.
The formulation of immunotherapeutic compositions and in particular vaccines with different adjuvants may affect the antibody response differently. Formulations that have been used to adjuvant capsomeres include cholera toxin, Escherichia coli enterotoxin, CpG, complete Freund's, and alum or alum in combination with monophosphoryl A. The most important issue in any adjuvant is its safety. Due to the toxicity, some adjuvants, such as complete Freund's adjuvant which causes strong local reaction, are only used in preclinical studies although they are very efficient in adjuvanting weak antigens.
Currently, only very few vaccine adjuvants are licensed for use in humans. Although both MF59 and aluminum salts have been approved in Europe, only aluminum salts have been used in licensed human vaccines in the United States. Billions of doses of vaccines containing aluminum salts have been shown to elicit early, high and long lasting antibody titers after a single immunization.
Aluminium salts have several disadvantages for use as adjuvants inclusive of a bias in the type of immune response elicited by aluminum salt adjuvants, instability to freezing and drying and inconsistencies in producing humoral immunity. Additionally, despite maintaining a good safety profile for more than seven decades, there have still been safety concerns regarding the use of aluminum salts. Symptoms such as erythema, allergic responses, hypersensitivity to contact, granulomatous inflammation and subcutaneous nodules as well as macrophagic myofascitis have been reported for patients who received an aluminum salt-containing vaccine. While aluminum salts offer an appropriate immune enhancement for some types of vaccines, they are clearly not adequate for all. This can also apply to MF59. MF59 consists of squalene, Tween 80, and Span 85 in sodium citrate buffer. There have been two reported cases of hypersensitivity reaction to the Tween 80.